Leukotriene A4 hydrolase inhibitors

ABSTRACT

The present invention relates to leukotriene A 4  hydrolase inhibitors containing compounds represented by the formula [I] or salts thereof as active ingredients,                    
     wherein R 1  represents hydrogen, alkyl, phenylalkyl, alkanoyl or benzoyl; R 2  and R 3  each represent hydrogen or alkyl; R 4  represents hydroxyl, alkoxy, phenylalkoxy, amino, alkylamino or phenylalkylamino; R 5  represents phenylalkyl or naphthylalkyl; “Z” represents sulfur or oxygen; “A” represents alkylene; and “n” represents 0, 1 or 2; providing that the phenyl ring in R 1  can be substituted by alkyl, alkoxy or halogen, and that the phenyl ring or the naphthyl ring in R 5  can be substituted by alkyl, cycloalkyl, alkoxy, alkylthio or halogen.

This application is a 371 of PCT/JP98/01300 filed Mar. 25, 1998.

TECHNICAL FIELD

The present invention relates to leukotriene A₄ hydrolase inhibitorscontaining mercaptoacylproline derivatives as active ingredients andparticularly provides useful drugs as therapeutic agents forinflammatory diseases such as rheumatic diseases.

BACKGROUND ART

Leukotriene A₄ (hereinafter abbreviated as LTA₄) hydrolase, which is oneof epoxide hydrolases, is a metal-containing enzyme which requires zincin its active center.

LTA₄ hydrolase plays a catalyst-like role on biochemical conversion fromLTA₄ into leukotriene B₄ (hereinafter abbreviated as LTB₄), which is astrong pro-inflammatory substance.

LTB₄ is an arachidonic acid metabolite which is produced in5-lipoxygenase pathway, is biosynthesized in various cells includingmast cell, neutrophil, monocyte, macrophage, etc., and plays a role asan important mediator in inflammation. LTB₄ induces chemotaxis,aggregation and degranulation of leukocyte and accumulation ofpolymorphonuclear leukocyte, and accelerates blood-vessel permeabilityand edema formation. For this reason, it was reported that particularlyhigh level of LTB₄ is detected at lesion sites in inflammatory diseasessuch as rheumatic diseases (J. Clin. Invest., 66, 1166-1170 (1980)),psoriasis (Br. J. Pharmacol., 83, 313-317 (1984)), inflammatory boweldiseases (Gastroenterology, 86, 453-460 (1984)) and gout (Lancet, 2,1122-1124 (1982)), and in sputum in cystic fibrosis (Lancet, 342,465-469 (1993)).

Accordingly, compounds which inhibit LTA₄ hydrolase are expected toprevent production of LTB₄ and exhibit therapeutic effects oninflammatory diseases such as rheumatic diseases.

Mercaptoacylproline derivatives, which are active ingredients in thepresent invention, are reported in U.S. Pat. No. 4,316,906 and J. Med.Chem., 31, 875-885 (1988) as antihypertensive agents having inhibitoryeffects on ACE. However, there is no report about LTA₄ hydrolaseinhibition effects of compounds having a substituent in 4th-position ofproline skeleton of these mercaptoacylproline derivatives. Compoundshaving a (lower cycloalkylphenyl)alkyl group in 4th-position of prolineskeleton are novel compounds which are not described in literature.

As mentioned above, the mercaptoacylproline derivatives are known tohave the inhibitory effects on ACE and to be useful as theantihypertensive agents. However, it is a very interesting subject tofind new medical use of these compounds.

The present inventors studied in order to find new medical use of theknown mercaptoacylproline derivatives and mercaptoacylprolinederivatives synthesized newly. As a result, these compounds were foundto exhibit excellent inhibitory activities on LTA₄ hydrolase.

DISCLOSURE OF THE INVENTION

The present invention relates to LTA₄ hydrolase inhibitors containingcompounds represented by the following general formula [I] or saltsthereof (hereinafter referred to as the present compounds) as activeingredients and novel compounds represented by the following generalformula [II] or salts thereof.

The groups defined above will be described in more detail. The loweralkyl means straight or branched lower alkyl having 1 to 6 carbon atomssuch as methyl, ethyl, propyl, butyl, hexyl or isobutyl. The loweralkanoyl means straight or branched alkanoyl having 2 to 6 carbon atomssuch as acetyl, propionyl, butyryl, hexanoyl, isobutyryl or pivaloyl.The lower alkoxy means straight or branched lower alkoxy having 1 to 6carbon atoms such as methoxy, ethoxy, propoxy, butoxy or hexyloxy. Thelower cycloalkyl means cyclic lower cycloalkyl having 3 to 8 carbonatoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cycloheptyl or cyclooctyl. The halogens atom means fluorine, chlorine,bromine and iodine. The lower alkylene means straight or branched loweralkylene having 1 to 6 carbon atoms such as methylene, ethylene,propylene or butylene.

Preferred examples of the above-mentioned compounds include thefollowings.

Compounds of the above general formula [I] wherein R¹ represents ahydrogen atom, a lower alkanoyl group or a benzoyl group, particularlypreferably a hydrogen atom, and salts thereof.

Compounds of the above general formula [I] wherein R² represents ahydrogen atom or a lower alkyl group, particularly preferably a hydrogenatom, and salts thereof.

Compounds of the above general formula [I] wherein R³ represents ahydrogen atom or a lower alkyl group, particularly preferably a methylgroup, and salts thereof.

Compounds of the above general formula [I] wherein R⁴ represents ahydrogen group or a lower alkyl group, particularly preferably ahydroxyl group, and salts thereof.

Compounds of the above general formula [I] wherein R⁵ represents aphenyl group or a naphthyl group which can be substituted by a loweralkyl group, a lower cycloalkyl group, a lower alkoxy group or a loweralkylthio group, more preferably a phenyl group which can be substitutedby a lower alkyl group or a lower cycloalkyl group, particularlypreferably a phenyl group which can be substituted by an isopropylgroup, a t-butyl group or a cyclohexyl group, and salt thereof.

Compounds of the above general formula [I] wherein “Z” represents asulfur atom or an oxygen atom, particularly preferably a sulfur atom,and salt thereof.

Compounds of the above general formula [I] wherein “A” represents alower alkylene group, particularly preferably a methylene group, andsalts thereof.

Compounds of the above general formula [I] wherein “n” represents 0, 1or 2, particularly preferably 1, and salts thereof.

Specific examples of particularly preferred compounds are(4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,(4S)-4-(4-t-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand(4S)-4-(4-cyclohexylbenzylthio-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,which are represented by the following formulae [III], [IV] and [V],respectively, and salts thereof.

Among the novel compounds represented by the above general formula [II],the following compounds are exemplified as preferred compounds.

Compounds of the above general formula [II] wherein R⁶ represents ahydrogen atom, a lower alkanoyl group or a benzoyl group, particularlypreferably a hydrogen atom, and salts thereof.

Compounds of the above general formula [II] wherein R⁷ represents ahydrogen atom or a lower alkyl group, particularly preferably a hydrogenatom, and salts thereof.

Compounds of the above general formula [II] wherein R⁸ represents ahydrogen atom or a lower alkyl group, particularly preferably a methylgroup, and salts thereof.

Compounds of the above general formula [II] wherein R⁹ represents ahydroxyl group or a lower alkoxy group, particularly preferably ahydroxyl group, and salts thereof.

Compounds of the above general formula [II] wherein R¹⁰ represents alower cycloalkyl group, particularly preferably a cyclohexyl group, andsalts thereof.

Compounds of the above general formula [II] wherein “Z” represents asulfur atom or an oxygen atom, particularly preferably a sulfur atom,and salts thereof.

Compounds of the above general formula [II] wherein “A” represents alower alkylene group, particularly preferably a methylene group, andsalts thereof.

Compounds of the above general formula [II] wherein “n” represents 0, 1or 2, particularly preferably 1, and salts thereof.

Specific examples of particularly preferred compounds are(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,which is represented by the following formula [V], and salts thereof.

The above-mentioned salts can be any pharmaceutically acceptable salts.Examples thereof are hydrochlorides, sulfates, phosphates, lactates,maleates, fumarates, oxalates, methanesulfonates,para-topluenesulfonates, etc. In addition, diastereo isomers and opticalisomers are present in the above-mentioned compounds, and all of themare included in the present invention. Furthermore, the above-mentionedcompounds can be in the form of solvate, for example, hydrates, adductswith ethanol, etc.

In order to examine the utility of the mercaptoacylproline derivativesrepresented by the general formula [I] (hereinafter referred to as thepresent compound), studies were made on effects of the present compoundson LTA₄ hydrolase. The details will be shown in the pharmacological testdescribed hereinafter. As the result of studies of the present compoundsusing LTA₄ as a substrate and measuring an amount of LTA₄ formed by anenzymatic reaction as an indication, the present compounds exhibitedhigh inhibitory activities on LTA₄ hydrolase. Accordingly, the presentcompounds are expected to be useful for treatment of various diseases inwhich LTA₄ participates, particularly inflammatory diseases such asrheumatic diseases, psoriasis, inflammatory bowel diseases, gout andcystic fibrosis.

The results of the pharmacological test are those regarding onlycompounds wherein R¹ represents a hydrogen atom and R⁴ represents ahydroxyl group, so-called an active compounds, among the compoundsrepresented by the general formula [I]. However, these compounds, ofcourse, can be administered in the form of prodrugs. Accordingly, it isa matter of course that compounds wherein R¹ is a group widely used as aprotective group of a mercapto group, that is, a lower alkyl group, aphenyl-lower alkyl group, a lower alkanoyl group or a benzoyl group arealso included in the present invention. In addition, a technique forconverting a carboxyl group into ester or amide to form prodrugs is alsowidely used. Compounds wherein R⁴ represents a lower alkoxy group, aphenyl-lower alkoxy group, an amino group, a lower alkylamino group or aphenyl-lower alkylamino group are also, of course, included in thepresent invention.

The present compound can be administered orally or parenterally.Examples of dosage forms are tablets, capsules, granules, powders,injections, etc. The present compound can be formulated intopreparations by the conventional methods. For example, oral preparationssuch as tablets, capsules, granules and powders can be produced byadding optionally diluents such as lactose, crystalline cellulose,starch and vegetable oil; lubricants such as magnesium stearate andtalc; binders such as hydroxypropylcellulose and polyvinyl pyrrolidone;disintegrator such as calcium carboxymethylcellulose or low-substitutedhydroxypropylmethylcellulose; coating agent such ashydroxypropylmethylcellulose, macrogol or silicone resin; or gelatinfilm forming agent.

The dosage of the present compound can be selected suitably according tothe symptom, age, dosage form and the like. In case of the oralpreparation, the present compound can be administered once to severaltimes per day with a daily dose of 0.1 to 5000 mg, preferably 1 to 1000mg.

BEST MODE FOR CARRYING OUT THE INVENTION

Examples of preparations and results of pharmacological test of thepresent invention are shown below. These examples do not limit the scopeof the invention, but are intended to make the invention more clearlyunderstandable.

Preparation of Compounds REFERENCE EXAMPLE 1(4S)-4-(4-cyclohexylbenzylthio)-L-proline (reference compound No. 1)

To (4S)-4-mercapto-L-proline hydrochloride (300 mg) is added 2 N sodiumhydroxide (1.6 ml) aqueous solution, and the mixture is stirred at 0° C.A solution of 4-cyclohexylbenzyl chloride (340 mg) in a mixed solvent ofethanol (5 ml)/chloroform (1 ml) is added thereto, and the mixture isstirred at room temperature overnight. The reaction mixture isconcentrated under reduced pressure, and deposited crystals are filteredoff. The crystals are washed with water, ethanol and diethyl ethersuccessively to give 470 mg (91%) of the titled compound.

mp 208.9-210.3° C.

EXAMPLE 11-[(2S)-3-Benzoylthio-2-methylpropionyl]-(4S)-4-(4-cyclohexylbenzylthio)-L-proline(compound No. 1)

Dimethylformamide (4.5 ml) is added to(4S)-4-(4-hexylbenzylthio)-L-proline (430 mg), and the mixture is cooledto 0° C. To the mixture are added successively triethylamine (0.21 ml)and 4-nitrophenyl (2S)-3-(benzoylthio)-2-methylpropionate, and theobtained mixture is stirred at room temperature overnight. To thereaction mixture is added 10% citric acid, and the whole is extractedwith ethyl acetate. The organic layer is washed with water and asaturated sodium chloride aqueous solution successively and dried oversodium sulfate. The residue obtained by concentration under reducedpressure is purified by silica gel column chromatography to give 580 mg(81%) of the titled compound as an amorphous substance.

[α]_(D) ²⁰−73.4° (c=0.5, methanol)

IR (film, cm⁻¹) 2924, 1744, 1659, 1447, 1207, 915, 755, 689

EXAMPLE 2(4S)-4-(4-cyclohexybenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline(compound No. 2)

Under a nitrogen atmosphere, 28% aqueous ammonia (9 ml) is added to1-[(2S)-3-benzoylthio-2-methylpropionyl]-(4S)-4-(4-cyclohexylbenzylthio)-L-proline(500 mg), and the mixture is stirred at room temperature for one hour.Ethyl acetate is added to the reaction mixture, and the whole isextracted with water. The aqueous layer is cooled to 0° C., 6 Nhydrochloric acid is added thereto to adjust pH to 2, and the whole isextracted with ethyl acetate. The organic layer is washed with asaturated sodium chloride aqueous solution and dried over magnesiumsulfate. The residue obtained by concentration under reduced pressure ispurified by silica gel column chromatography to give 340 mg (87%) of thetitled compound as an amorphous substance.

[α]_(D) ²⁰−50.4° (c=0.5, methanol)

IR (film, cm⁻¹) 2924, 1736, 1641, 1612, 1463, 1446, 756

(4S)-4-Mercapto-L-proline hydrochloride and 4-nitrophenyl(2S)-3-(benzoylthio)-2-methylpropionate, which were used as rawmaterials in the above-mentioned Preparation of Compounds, are describedin J. Org. Chem., 46, 4182-4187 (1981) and Japanese Laid-open PatentPublication 301840/1996, respectively.

Pharmacological Test

Izumi et al. had reported a method of measuring LTA₄ hydrolase activityby measuring an amount of LTB₄ produced by an enzymatic reaction usingLTA₄ as a substrate (Biochem. Biophys. Res. Commun., 135, 139-145(1986)). Effects of the present compounds on LTA₄ hydrolase wereexamined according to the method described in the literature.

Experimental Method

An enzyme preparation used in this pharmacological test was prepared byextracting from guinea pig lung without purification according to themethod of Izumi et al. (Biochem. Biophys. Res. Commun., 135, 139-145(1986)) and the method of Evans et al. (Biochem. Biophys. Acta, 840,43-50 (1985)). The experimental method is as follows:

Lungs were excised from a Hartley guinea pig (body weight: 330 g). Thelungs were homogenized in phosphoric acid buffer (50 mM, pH 7.4,containing 1 mM ethylenediaminetetraacetic acid (EDTA) and 1 mMdithiothreitol (DTT) having weight three times that of the lungs underice-cooling. The homogenate was centrifuged at low speed (800×g) for 20minutes, centrifuged at high speed (10,000×g) for 20 minutes andultracentrifuged (100,000×g) for 60 minutes to give a supernatant. Thesupernatant was brought to 40% saturation by adding a saturated aqueousammonium sulfate solution (pH 7.0-7.2, containing 1 mM DTT) dropwiseunder ice-cooling and centrifuged at high speed (10,000×g) for 20minutes. The resulting supernatant was brought to 70% saturation byadding a saturated aqueous ammonium sulfate solution (pH 7.0-7.2,containing 1 mM DTT) dropwise and centrifuged at high speed (10,000×g)for 20 minutes. The obtained pellet was dissolved in 2 ml of Tris-aceticacid buffer (20 mM, pH 7.8, containing 1 mM DTT) and dialyzed in 2liters of the solution to give the enzyme preparation.

LTA₄ used, which is the substrate, was prepared by hydrolyzing LTA₄methyl ester and dissolved in ethanol.

In order to examine effects of the test compounds on the enzymepreparation, reactions were performed under the following conditionusing mixed solutions consisting of the composition shown in Table 1.

TABLE 1 HEPES buffer 50 mM, pH 7.8 Enzyme preparation 0.4-0.6 mg proteinLTA₄ 63 μM DTT aqueous solution 3 mM Test compounds 10⁻⁸-10⁻³ M

The above-mentioned solution (50 μl) was incubated at 37° C. for oneminute. To the reaction mixture was added 100 μl of a mixed liquid ofacetonitrile-ethanol-acetic acid (150:50:3, volume ratio) underice-cooling. The mixture was allowed to stand at −20° C. for 30 minutesand centrifuged at high speed (10,000×g) for five minutes to give asupernatant. An amount of LTB₄ produced in the supernatant was measuredby high-speed liquid chromatography.

The degree of the inhibitory effect of each test compound on LTA₄hydrolase is expressed by the inhibition rate calculated by thefollowing equation.${{Inhibition}\quad {rate}\quad (\%)} = {\frac{A - B}{A} \times 100}$

A: amount of LTB₄ formed in the absence of the test compound

B: amount of LTB₄ formed in the presence of the test compound

Results

Experimental results obtained by using the following compounds asrepresentative examples of the test compound are shown in Table 2.

Compound a:1-[(2S)-3-mercapto-2-methylpropionyl]-(4S)-4-(2-methylbenzylthio)-L-proline

Compound b:(4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

Compound c:(4S)-4-(4-isopropylphenyethylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

Compound d:(4R)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

Compound e:(4R)-4-(4-isopropylbenzyloxy)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

Compound f:(4S)-4-(4-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

Compound g:1-[(2S)-3-mercapto-2-methylpropionyl]-(4S)-4-[4-(methylthio)benzylthio]-L-proline

Compound h:(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline

The results are represented in concentration of the compounds requiredto inhibit LTA₄ hydrolase activity by 50%, i.e., IC₅₀.

TABLE 2 IC₅₀ (M) Compound a 8.4 × 10⁻⁷ Compound b 5.2 × 10⁻⁸ Compound c7.9 × 10⁻⁷ Compound d 2.9 × 10⁻⁷ Compound e 8.0 × 10⁻⁷ Compound f 3.1 ×10⁻⁸ Compound g 1.2 × 10⁻⁷ Compound h 3.4 × 10⁻⁸

As shown in Table 2, the present compounds were found to inhibit theLTA₄ hydrolase activity remarkably at the low concentrations.

Since the above-mentioned pharmacological test shows that the presentcompounds have the excellent inhibitory effects on LTA₄ hydrolase, thecompounds are expected to be, in particular, therapeutic agents forinflammatory diseases such as rheumatic diseases, psoriasis,inflammatory intestinal diseases, gout and cystic fibrosis, in whichLTB₄ is concerned.

Industrial Applicability

The present invention relates to leukotriene A₄ hydrolase inhibitorscontaining mercaptoacylproline derivatives as active ingredients andparticularly provides therapeutic agents for inflammatory diseases suchas rheumatic diseases, psoriasis, inflammatory intestinal diseases, goutand cystic fibrosis, in which LTB₄ is concerned.

What is claimed is:
 1. A method of treating a patient having aninflammatory disease comprising administering an effective leukotrieneA₄ hydrolase inhibiting amount of a compound of the formula I or apharmaceutically acceptable salt thereof,

wherein R¹ represents a hydrogen atom, a lower alkyl group, aphenyl-lower alkyl group, a lower alkanoyl group or a benzoyl group, andeach phenyl ring of the phenyl-lower alkyl group and the benzoyl groupcan be substituted by a lower alkyl group, a lower alkoxy group or ahalogen atom; R² and R³ each represent a hydrogen atom or a lower alkylgroup; R⁴ represents a hydroxyl group, a lower alkoxy group, aphenyl-lower alkoxy group, an amino group, a lower alkylamino group or aphenyl-lower alkylamino group; R⁵ represents a phenyl group or anaphthyl group, and the phenyl group and the naphthyl group can besubstituted by a lower alkyl group, a lower cycloalkyl group, a loweralkoxy group, a lower alkylthio group or a halogen atom; “Z” representsa sulfur atom or an oxygen atom; “A” represents a lower alkylene group;and “n” represents 0, 1 or
 2. 2. The method of claim 1, wherein in saidcompound of the formula I or a pharmaceutically acceptable salt thereof,R¹ represents a hydrogen atom, a lower alkanoyl group or a benzoylgroup; R² and R³ each represent a hydrogen atom or a lower alkyl group;R⁴ represents a hydroxyl group or a lower alkoxy group; R⁵ represents aphenyl group or a naphthyl group, and the phenyl group can besubstituted by a lower alkyl group, a lower cycloalkyl group, a loweralkoxy group or a lower alkylthio group; “Z” represents a sulfur atom oran oxygen atom; “A” represents a lower alkylene group; and “n”represents
 1. 3. The method of claim 1, wherein said compound of theformula I is selected from the group consisting of(4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,(4S)-4-(4-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand pharmaceutically acceptable salts of said compounds.
 4. A method oftreating a patient having a rheumatic disease comprising administeringan effective leukotriene A₄ hydrolase inhibiting amount of a compound ofthe formula I or a pharmaceutically acceptable salt thereof,

wherein R¹ represents a hydrogen atom, a lower alkyl group, aphenyl-lower alkyl group, a lower alkanoyl group or a benzoyl group, andeach phenyl ring of the phenyl-lower alkyl group and the benzoyl groupcan be substituted by a lower alkyl group, a lower alkoxy group or ahalogen atom; R² and R³ each represent a hydrogen atom or a lower alkylgroup; R⁴ represents a hydroxyl group, a lower alkoxy group, aphenyl-lower alkoxy group, an amino group, a lower alkylamino group or aphenyl-lower alkylamino group; R⁵ represents a phenyl group or anaphthyl group, and the phenyl group and the naphthyl group can besubstituted by a lower alkyl group, a lower cycloalkyl group, a loweralkoxy group, a lower alkylthio group or a halogen atom; “Z” representsa sulfur atom or an oxygen atom; “A” represents a lower alkylene group;and “n” represents 0, 1 or
 2. 5. The method of claim 4, wherein in saidcompound of the formula I or a pharmaceutically acceptable salt thereof,R¹ represents a hydrogen atom, a lower alkanoyl group or a benzoylgroup; R² and R³ each represent a hydrogen atom or a lower alkyl group;R⁴ represents a hydroxyl group or a lower alkoxy group; R⁵ represents aphenyl group or a naphthyl group, and the phenyl group can besubstituted by a lower alkyl group, a lower cycloalkyl group, a loweralkoxy group or a lower alkylthio group; “Z” represents a sulfur atom oran oxygen atom; “A” represents a lower alkylene group; and “n”represents
 1. 6. The method of claim 4, wherein said compound of theformula I is selected from the group of(4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,(4S)-4-(4-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-proline,(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand pharmaceutically acceptable salts of said compounds.
 7. Apharmaceutically composition for treating inflammatory diseasescomprising a carrier and a compound of the formula I or apharmaceutically acceptable salt thereof,

wherein R¹ represents a hydrogen atom, a lower alkyl group, aphenyl-lower alkyl group, a lower alkanoyl group or a benzoyl group, andeach phenyl ring of the phenyl-lower alkyl group and the benzoyl groupcan be substituted by a lower alkyl group, a lower alkoxy group or ahalogen atom; R² and R³ each represent a hydrogen atom or a lower alkylgroup; R⁴ represents a hydroxyl group, a lower alkoxy group, aphenyl-lower alkoxy group, an amino group, a lower alkylamino group or aphenyl-lower alkylamino group; R⁵ represents a phenyl group or anaphthyl group, and the phenyl group and the naphthyl group can besubstituted by a lower alkyl group, a lower cycloalkyl group, a loweralkoxy group, a lower alkylthio group or a halogen atom; “Z” representsa sulfur atom or an oxygen atom; “A” represents a lower alkylene group;and “n” represents 0, 1 or
 2. 8. The pharmaceutical composition of claim7 for treating a rheumatic disease.
 9. The pharmaceutical composition ofclaim 8 wherein in said compound of the formula I or pharmaceuticalacceptable salt thereof, R¹ represents a hydrogen atom, a lower alkanoylgroup or a benzoyl group; R² and R³ each represent a hydrogen atom or alower alkyl group; R⁴ represents a hydroxyl group or a lower alkoxygroup; R⁵ represents a phenyl group or a naphthyl group, and the phenylgroup can be substituted by a lower alkyl group, a lower cycloalkylgroup, a lower alkoxy group or a lower alkylthio group; “Z” represents asulfur atom or an oxygen atom; “A” represents a lower alkylene group;and “n” represents
 1. 10. The pharmaceutical composition of claim 9wherein said compound is selected from the group consisting of(4S)-4-(4-isopropylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand pharmaceutically acceptable salts thereof.
 11. The pharmaceuticalcomposition of claim 9 wherein said compound is selected from the groupconsisting of(4S)-4-(4-t-butylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand pharmaceutically acceptable salts thereof.
 12. The pharmaceuticalcomposition of claim 10 wherein said compound is selected from the groupconsisting of(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineand pharmaceutically acceptable salts thereof.
 13. A compoundrepresented by the following general formula [II] or a salt thereof,

wherein R⁶ represents a hydrogen atom, a lower alkyl group, aphenyl-lower alkyl group, a lower alkanoyl group or a benzoyl group, andeach phenyl ring of the phenyl-lower alkyl group and the benzoyl groupcan be substituted by a lower alkyl group, a lower alkoxy group or ahalogen atom; R⁷ and R⁸ each represent a hydrogen atom or a lower alkylgroup; R⁹ represents a hydroxyl group, a lower alkoxy group, aphenyl-lower alkoxy group, an amino group, a lower alkylamino group or aphenyl-lower alkylamino group; R¹⁰ represents a lower cycloalkyl group;“Z” represents a sulfur atom or an oxygen atom; “A” represents a loweralkylene group; and “n” represents 0, 1 or
 2. 14. The compound of claim13 which is(4S)-4-(4-cyclohexylbenzylthio)-1-[(2S)-3-mercapto-2-methylpropionyl]-L-prolineor a pharmaceutically acceptable salt thereof.